Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma
Authors: Maartje W. Rohaan, Troels H. Borch, Joost H. van den Berg, Özcan Met, Rob Kessels, Marnix H. Geukes Foppen, Joachim Stoltenborg Granhøj, Bastiaan Nuijen, Cynthia Nijenhuis, Inge Jedema, Maaike van Zon, Saskia Scheij, Jos H. Beijnen, Marten Hansen, Carlijn Voermans, Inge M. Noringriis, Tine J. Monberg, Rikke B. Holmstroem, Lidwina D.V. Wever, Marloes van Dijk, Lindsay G. Grijpink-Ongering, Ludy H.M. Valkenet, Alejandro Torres Acosta, Matthias Karger, Jessica S.W. Borgers, Renske M.T. ten Ham, Valesca P. Retèl, Wim H. van Harten, Ferry Lalezari, Harm van Tinteren, Astrid A.M. van der Veldt, Geke A.P. Hospers, Marion A.M. Stevense-den Boer, Karijn P.M. Suijkerbuijk, Maureen J.B. Aarts, Djura Piersma, Alfons J.M. van den Eertwegh, Jan-Willem B. de Groot, Gerard Vreugdenhil, Ellen Kapiteijn, Marye J. Boers-Sonderen, W. Edward Fiets, Franchette W.P.J. van den Berkmortel, Eva Ellebaek, Lisbet R. Hölmich, Alexander C.J. van Akkooi, Winan J. van Houdt, Michel W.J.M. Wouters, Johannes V. van Thienen, Christian U. Blank, Aafke Meerveld-Eggink, Sebastian Klobuch, Sofie Wilgenhof, Ton N. Schumacher, Marco Donia, Inge Marie Svane, John B.A.G. Haanen
Journal: New England Journal of Medicine (2022)

Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival.A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression.In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).